Chronic prostatitis and chronic pelvic pain syndrome: a new consensus guideline
Prostate cancer is the second most common cause of Staus Prostatitis death in US men. Along with initial therapy using surgery, radiotherapy, or cryotherapy, hormonal therapy is the mainstay of treatment. For men with advanced metastatic disease, docetaxel-based chemotherapy is US Food and Drug Administration FDA -approved, and provides a significant survival advantage.
This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy. The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counterintuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive Staus Prostatitis.
However, prostate cancer arises in a relatively unique organ and may express a number of proteins antigens against which an immune response can be generated. Staus Prostatitis importantly, several of these agents have Staus Prostatitis demonstrated a significant survival benefit in randomized controlled clinical trials, and one agent in particular Sipuleucel-T, Dendreon Corporation, Seattle, WA Staus Prostatitis be FDA-approved in Staus Prostatitis update summarizes recent clinical developments in the field of prostate cancer immunotherapy, with a focus on dendritic cell vaccines, virus-based vaccines, DNA-based vaccines, and cell-based vaccines.
In addition, the notion of agents that target immune checkpoints is introduced. Enthusiasm for prostate cancer immunotherapy is founded upon its potential to mediate targeted, specific, tumor cell destruction without significant systemic toxicity; however, this has yet to Staus Prostatitis fully realized in the clinical arena. Cancer immunotherapy refers generally to approaches that attempt Staus Prostatitis treat cancer by activating an immune response directed Staus Prostatitis tumor cells while overcoming tumor-induced tolerance.
Although prostate cancer has Staus Prostatitis traditionally been thought of as a disease amenable to immunological therapies, this concept has recently been challenged for several reasons. First, prostate cancer is a slow-growing disease that may give a stimulated immune system time to generate an antitumor response while overcoming immunosuppressive factors.
Second, recent evidence suggests that prostate cancer is more immunogenic that previously thought, having the ability to induce spontaneous autoantibodies [ 1 ]. Third, both proteomic and microarray analyses have identified several relatively tissue-specific proteins Staus Prostatitis may serve as prostate tumor antigens. Finally, abundant laboratory data suggest that antitumor immune responses can be elicited against prostate cancer cells, especially when active immunotherapy is combined with approaches that mitigate tolerance eg, immune checkpoint blockade, androgen ablation, or radiotherapy.
For these reasons, and because of the relative safety of immunotherapy, there are currently multiple immunological strategies in clinical development for prostate cancer Table 1. The most recent developments in this field are reviewed here.
A PubMed search for English-language manuscripts related to prostate cancer immunotherapy Staus Prostatitis conducted.
As specified by journal guidelines, Staus Prostatitis recent articles within the past 2 years were reviewed. This update focuses primarily on agents and approaches that are being tested in a clinical trial setting.
In this approach, cells are cultured with a proprietary protein cassette, Staus Prostatitis fusion protein between the target antigen prostatic acid phosphatase [PAP] and granulocyte monocyte colony stimulating factor GM-CSF [ 2 ].
Mechanistically, GM-CSF is intended to activate and mature monocytes toward dendritic cells, which present their target antigen to T lymphocytes in a stimulatory context. Activated T lymphocytes then traffic widely throughout the body, theoretically recognizing and killing tumor cells through a variety of nonredundant molecular programs. The target antigen PAP was chosen based on interesting preclinical animal studies [ 3 ], which showed that a PAP-targeted Staus Prostatitis could break tolerance Staus Prostatitis intact animals, inducing significant prostatitis in intact hosts.
In addition, prostatic antigen represents a unique target protein against which immune responses can be quantified using a variety of methods. Several clinical trials using this agent have been published, with initial studies demonstrating safety and suggesting some degree of efficacy [ 4 ].
Encouraging results have come from Staus Prostatitis trial performed in patients with metastatic castrate-resistant prostate cancer CRPC who were either asymptomatic or mildly symptomatic. In this trial, Sipuleucel-T three doses 2 weeks apart was compared with placebo, with a randomization in favor of the immunotherapy arm. Staus Prostatitis, Sipuleucel-T showed a Staus Prostatitis survival advantage versus placebo Because overall survival was not the primary end point of this study, and the trial was rather small relative to typical phase III trials in prostate cancer, those results were not universally persuasive.
The results of the larger trial were consistent with earlier studies, showing a 4. The corresponding biological license application was amended in lateand a US Food and Drug Administration FDA decision regarding marketing is expected in the second quarter of Although the survival data in these trials appear robust and consistent, Staus Prostatitis should be noted that the comparator arm in each case was a placebo group, not chemotherapy using docetaxel, which has also been demonstrated to provide a survival advantage in men with CRPC [ 78 ].
This comparison can be justified by the notion that chemotherapy for prostate cancer is in many cases reserved for men with later stage symptomatic Staus Prostatitis, but that concept is not without controversy [ 9 ].
Cancer immunotherapy in general, and prostate cancer immunotherapy in particular, can be engineered using attenuated viral vectors. This Staus Prostatitis has a long history, and has the advantage that viral vectors can be engineered to carry large payloads.
In addition, and in contrast to the complexity of the cell-based approach described above, viral vaccines are also relatively easy to manufacture and distribute. These vectors are generally quite Staus Prostatitis in priming an immune response.
However, subsequent immunization results in responses more heavily directed against the viral backbone than against the encoded target antigen. Thus, a heterologous prime-boost strategy was investigated, in which vaccinia-based vectors were alternated with vectors based on a fowlpox backbone. In an Staus Prostatitis randomized clinical trial, it was determined that optimal immune responses were engendered when vaccinia-based vectors were used in the priming phase, followed by subsequent fowlpox boost [ 11 ].
A large number of trials utilizing this agent—both alone and in carefully considered combinations—have been completed, and these data are nicely reviewed in a recent publication by Madan et al. However, the most significant result in the development of ProstVac VF came only recently in the form of updated results from a clinical trial in which this agent was compared with placebo in a patient randomized phase II trial in men Staus Prostatitis minimally symptomatic CRPC.
Staus Prostatitis trial, designed similarly to the successful trials of Sipuleucel-T discussed above, was a randomized study with a primary end point of progression-free survival.
Initial analysis of this trial was less than encouraging, but as the data matured it became clear that there was a significant overall survival OS advantage associated with ProstVac VF treatment compared with placebo median survival However, these data Staus Prostatitis be viewed as hypothesis-generating, because OS was not the primary end Staus Prostatitis of the original trial.
The Staus Prostatitis of this study are instructive in that they point out the potential importance of OS as a primary end point in clinical immunotherapy trials for men with prostate cancer, as well as the relatively extensive time periods required for data to fully mature.
In that regard, a recently published Staus Prostatitis analysis of an earlier ProstVac VF trial is particularly noteworthy. Here, the authors showed that the prostate cancer patients who benefit from immunotherapy appear to Staus Prostatitis those with a greater overall predicted survival Staus Prostatitis quantified by an Staus Prostatitis of the Halabi nomogram [ 14 ]. Although encouraging from the standpoint of patient Staus Prostatitis, these data are Staus Prostatitis somewhat discouraging in terms of clinical development, confirming the concept that these types of clinical trials can potentially take several years to mature.
This platform is one of the most flexible and straightforward available, but this flexibility comes at a price because such constructs are generally less immunogenic than, for example, viral-based vectors. This relatively modest immunogenicity, Staus Prostatitis with the notion that the barriers to successful immunotherapy for prostate cancer may be less formidable in a minimal disease setting, led McNeel et al. As is typical for immunotherapy studies, very little toxicity was noted, but immune responses against the target antigen could be demonstrated.
There was also a suggestion that the PSA doubling time of treated men Staus Prostatitis corresponding to a slowing of the rate of PSA risebut it is generally acknowledged that the clinical Staus Prostatitis of such changes is uncertain at the present time. The relative ease with which DNA-based vaccines can be Staus Prostatitis is encouraging; the vector used in this vaccine can theoretically be employed to compare several potential target antigens in a head-to-head manner.
Because cancer cells themselves are generally nonimmunogenic, antitumor immunity may be induced by intradermal Staus Prostatitis of cancer cells engineered to express a proinflammatory cytokine [ 16 ]. An agent known as prostate GVAX embodied this approach in the clinic. This whole-cell approach had several theoretical advantages, most notably that of presenting a large number of tumor antigens simultaneously.
The primary end Staus Prostatitis of these trials was Staus Prostatitis, but both studies were terminated early. VITAL-1 was closed because data from Staus Prostatitis unplanned interim analysis suggested that an OS benefit was unlikely to be realized. The mechanism for this imbalance in deaths has not been fully explained, but did not seem to result from excess toxicity in the immunotherapy arm.
However, further commercial development of this platform has been discontinued by the manufacturer. The principal obstacle to such approaches is obvious. In sharp contrast to vaccines used to prevent infectious diseases, prostate cancer patients have coexisted with their tumors for several years. Thus, the tumor and its associated stroma have evolved multiple mechanisms by which to evade immune attack [ 21 ].
Although a comprehensive discussion of these multiple escape mechanisms [ 22 ] is clearly beyond the scope of this update, the mechanism of Staus Prostatitis checkpoints is worthy of mention because agents targeting such checkpoints have advanced to the point of phase III trials in men with prostate cancer.
In a normal host, these checkpoints most likely serve to attenuate autoimmunity, preventing the organism from damaging self-tissues as a result of an overly exuberant immune response. Tumors have co-opted this mechanism, and prostate cancer-infiltrating lymphocytes appear to express a number of such molecules, most notably Staus Prostatitis lymphocyte antigen 4 CTLA-4 and programmed death-1 PD-1 [ 23 ]. A monoclonal antibody specific for CTLA-4 ipilimumab has been extensively evaluated for patients with metastatic melanoma.
These results are particularly noteworthy, because bona fide PSA responses were rarely reported in the Staus Prostatitis immunotherapy vaccine trials discussed above. Ambitiously, a randomized phase III trial of this agent has recently been initiated in patients with prostate cancer.
In contrast to many of the trials mentioned above, this study targets men with end-stage disease, that is, those with metastatic Staus Prostatitis who have not Staus Prostatitis to chemotherapy. The rationale for the choice of this patient population is that there is currently no standard approved treatment that Staus Prostatitis a reliable survival Staus Prostatitis after docetaxel failure [ 27 ]. This trial is somewhat innovative Staus Prostatitis that it includes Staus Prostatitis radiotherapy prior to immunotherapy in an effort to prime an antitumor Staus Prostatitis through release of antigen from irradiated tumor cells.
Although such trials include a number of patients with prostate cancer, a prostate cancer-specific trial has not yet been initiated. The Staus Prostatitis period covered by this report represents Staus Prostatitis promising era for prostate cancer immunotherapy.
Two Staus Prostatitis clinical trials using very different agents Sipuleucel-T and ProstVac VF independently demonstrated a statistically significant survival advantage over placebo in patients with metastatic CRPC. Significantly, the former trial may provide the basis for regulatory approval of Sipuleucel-T. In addition, smaller studies have provided clinical support for the notion that immunotherapy is most likely to be effective in men with less advanced disease, and have introduced the concept of DNA-based vaccination as an interesting and flexible platform.
Perhaps most Staus Prostatitis, the concept of immune checkpoint blockade is emerging as an alternative to traditional vaccination approaches, with a large randomized phase III study using ipilimumab currently Staus Prostatitis. In the future, it seems likely that clinical combinations Staus Prostatitis active immunotherapy with immune checkpoint Staus Prostatitis, or perhaps combinations involving conventional therapy in series or parallel with immunotherapy, may result in more effective treatment Staus Prostatitis men with prostate cancer.
Disclosure Dr. Charles G. Drake has served as a consultant for Amplimmune, Inc. He also has stock ownership in Amplimmune, Inc.
No other potential conflicts of interest relevant to this article were reported. National Center for Biotechnology InformationU. Curr Urol Rep. Author manuscript; available Staus Prostatitis PMC May Drake and Emmanuel S. Author information Copyright and Staus Prostatitis information Disclaimer. Corresponding author. Drake: ude. Antonarakis: ude. Copyright notice.
The publisher's final edited version of this article is available at Curr Urol Rep. See other articles in PMC that cite the published article. Abstract Prostate cancer is the second most common cause of cancer-related death in US men.